Guinea pigs that are either vitamin C deficient or fasted (vitamin C supplemented) are equivalent with respect to the mechanisms responsible for decreased collagen and proteoglycan synthesis. Circulating insulin-like growth factor binding proteins (IGFBPs) induced during scurvy and fasting inhibit these functions in cultured connective tissue cells because they interfere with IGF-I action. They appear to be in vivo inhibitors since they are induced prior to decreased collagen gene expression in fasted and scorbutic guinea pigs and are taken up by connective tissues. We are determining whether other effects of vitamin C deficiency are mediated through anorexia and induction of IGFBPs or whether different mechanisms are involved. Iron deficiency developed in scorbutic animals prior to weight loss and probably resulted from reduced uptake of iron in the absence of ascorbate. There were changes in the expression of ferritin and transferrin receptor which, in cell culture, are regulated through an iron response protein. Expression of the iron response protein itself decreased, however, suggesting that regulation of iron-related genes during iron deficiency differs in vivo compared to cell culture. Loss of alkaline phosphatase bone isoenzyme activity accounted for most of the decrease in total activity in serum during scurvy. There was a bone tissue-specific decrease in alkaline phosphatase activity, protein and mRNA that was not related to anorexia. Therefore, expression of alkaline phosphatase and collagen in bone are regulated through different mechanisms during vitamin C deficiency.